Method for preparing styryl pyrazole, isoxazole and isothiazole derivatives

ABSTRACT

The invention concerns a method for synthesizing styryl isoxazole, styryl pyrazole and styryl isothazole derivatives in a synthesis step followed by a recrystallization in a basic alcohol medium.

FIELD OF THE INVENTION

The present invention relates to a novel method for synthesizing styrylisoxazole, styryl pyrazole and styryl isothiazole derivatives.

The subject of the present invention is in particular a method forproducing compounds of the styryl isoxazole, styryl pyrazole and styrylisothiazole family in a synthesis step followed by recrystallizationfrom a basic alcoholic medium, serving as a dehydration and apurification. This method relates in particular to the production of(E)-5-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)vinyl]-3-methylisoxazolealso called 5-[β-(4′-hydroxy-3′,5′-bis-(1,1-dimethylethyl)phenyl)ethenyl]-3-methylisoxazole.

BACKGROUND OF THE INVENTION

Styryl isoxazole, styryl pyrazole and styryl isothiazole compounds, andin particular(E)-5-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)vinyl]-3-methylisoxazole,have been described in patent EP 0 245 825. These compounds, which are5-lipoxygenase and cyclooxygenase inhibitors, can be used in apharmaceutical composition. They also have sunscreen properties. Inparticular, they are capable of entering into the composition ofpharmaceutical formulations for the treatment of inflammation,arthritis, ulcers, allergies, asthma, psoriasis, cardiovascular statesin mammals. They are also used in compositions for protecting againstultraviolet light.

The synthesis of styryl isoxazole derivatives which is described inpatent EP 0 245 825 may be carried out according to three approaches. Inparticular, in the case of(E)-5-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)vinyl]-3-methylisoxazole,the following three synthesis schemes are possible:

I Wittig reaction between the aldehyde(3,5-di-tert-butyl-4-hydroxybenzaldehyde) and 3,5-di-methylisoxazoletriphenylphosphonium

II Two-step method comprising:

-   -   A reaction between the aldehyde (3,5-di        -tert-butyl-4-hydroxybenzaldehyde) and the lithium salt of        3,5-dimethylisoxazole followed by chromatography on a silica gel        column.    -   A second step comprising the treatment of the product resulting        from the first step with hydro-chloric acid in methanol to give,        after purification on a silica gel column, the desired compound        with a yield of 49%.

III A third approach consists in reacting the aldehyde(3,5-di-tert-butyl-4-hydroxybenzaldehyde) with a 3-carboxylatederivative of isoxazole. After condensation, a dehydration and adecarboxylation are carried out.

The same synthesis schemes make it possible to obtain the styrylpyrazole and styryl isothiazole derivatives.

While the prior art methods make it possible to obtain the styrylisoxazole, styryl pyrazole and styryl isothiazole derivatives, they havethe disadvantage of requiring the use of several steps and/or ofpurifications by chromatography in order to obtain a pure product.

SUMMARY OF THE INVENTION

The applicant set itself the objective of developing a method forpreparing styryl isoxazole, styryl pyrazole and styryl isothiazolederivatives comprising a limited number of steps and making it possibleto obtain a product having satisfactory purity without the need to usecomplicated and/or expensive purification steps.

The method of synthesis according to the invention applies to thepreparation of compounds corresponding to formula (I) below

in which:

R₁, R₂, R₃, at the 2, 3, 4, 5 or 6 position of the phenyl ring, whichare identical or different, are chosen from: a hydrogen atom; C₁-C₆alkyls; C₂-C₆ alkenyls; C₂-C₆ alkynyls; halogens, C₁-C₆ haloalkyls; —OH;the groups —OR′, —SH, —SR′, —SeH, —SeR′, —C(O)R′, —NHC(O)R′, —C(S)R′,—NHC(S)R′, —CN in which R′ represents a group chosen from C₁-C₆ alkyls,C₂-C₆ alkenyls, C₂-C₆ alkynyls; the groups —C(O)OR″, —OC(O)R″, —NR″R′″in which R″ and R′″, which are identical or different, represent a groupchosen from a hydrogen atom, C₁-C₆ alkyls, C₂-C₆ alkenyls, C₂-C₆alkynyls;

X and Y represent a pair of atoms chosen from: (NR₄, N) (pyrazole ring),(O, N) (isoxazole ring), (S, N) (isothiazole ring), R₄ being chosenfrom: a hydrogen atom; C₁-C₆ alkyls; the groups CH₂—OR₅, the groupsC(O)OR₅ in which R₅ is chosen from a hydrogen atom, a C₁-C₆ alkyl group,a benzyl group;

the heterocycle is linked to the phenyl ring via its 3- or 5-position inthe case of the pyrazole ring, via its 5-position in the case of theisoxazole and isothiazole rings;

n represents an integer chosen from 0, 1, 2, 3, 4, 5 and 6;

Z, at the 3- or 4-position of the isoxazole, pyrazole or isothiazolering, represents a group chosen from: a hydrogen atom; C₁-C₆ alkyls;C₂-C₆ alkenyls; C₂-C₆ alkynyls; halogens, C₁-C₆ haloalkyls; —OH; thegroups —OR′, —SH, —SR′, —SeH, —SeR′, —C(O)R′, —NHC(O)R′, —C(S)R′,—NHC(S)R′, —CN in which R′ represents a group chosen from C₁-C₆ alkyls,C₂-C₆ alkenyls, C₂-C₆ alkynyls; the groups —C(O)OR″, —OC(O)R″, —NR″R′″in which R″ and R′″, which are identical or different, represent a groupchosen from a hydrogen atom, C₁-C₆ alkyls, C₂-C₆ alkenyls, C₂-C₆alkynyls.

The terms alkyl, alkenyl and alkynyl used in the present inventiondesignate either linear, branched or cyclic radicals.

The heterocycle represented by the formula below:

represents according to the invention a group chosen from:

Preferably, the method according to the present invention applies to thepreparation of the products corresponding to formula (I) above, in whichone or more of the conditions below are met:

R₁, R₂, R₃ are at the 3-, 4- or 5-position of the phenyl ring;

R₁, R₂, R₃ are chosen from: a hydrogen atom; C₁-C₆ alkyls; halogens;C₁-C₆ haloalkyls; —OH; the groups —OR′, in which R′ represents a groupchosen from C₁-C₆ alkyls; the groups —OC(O)R″, in which R″ represents agroup chosen from a hydrogen atom, C₁-C₆ alkyls;

X=O; Y=N;

n=0;

Z is at the 3-position of the heterocycle, Z represents a group chosenfrom: C₁-C₆ alkyls; halogens; C₁-C₆ haloalkyls.

Advantageously, at least one of the conditions below is met:

the heterocycle represented by formula:

is a Z-substituted derivative of 5-isoxazole;

R₁ at the 3-position is a tert-butyl group;

R₂ at the 4-position is a hydroxyl group;

R₃ at the 5-position is a tert-butyl group;

Z at the 3-position is a methyl group.

Still more preferably, the invention applies to the preparation of(E)-5-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)vinyl]-3-methylisoxazole.

The method which is the subject of the present invention ischaracterized in that it comprises at least one step consisting intreating the product corresponding to formula (II) below in which R₁,R₂, R₃, X, Y, Z and n have the same definition as in formula (I) above,in alcohol in the presence of a base to give the product of formula (I):

A and B being chosen such that one of A and B is H, the other being —OH.

In the case of the derivatives of formula (I) in which n=0, the methodis similar to that developed by Warnert Lambert in patent EP 0 245 825in that it comprises the passage via a common intermediate, but itdiffers therefrom in the number of steps, the treatment and thepurification. Indeed, the alcohol (II) is subjected to a treatment in abasic alcoholic medium with the double objective of: 1) dehydrating thehydroxyl (II), 2) crystallizing the product (I) and thereby removing theimpurities in the mother liquors, which makes it possible to avoid acolumn chromatography. Recrystallization from an alcoholic medium canoptionally complete this method in order to give the product (I).

Compared with the prior art methods, the method according to theinvention is distinguishable by the following advantages: a betteryield, a small number of steps, a better feasibility on an industrialscale.

Preferably, the compound of formula (II) corresponds to formula (IIa)below in which R₁, R₂, R₃, X, Y and Z have the same definition as informula (I):

This variant represents the case where A=OH, B=H.

Advantageously, according to this variant of the invention, in the casewhere X=O and Y=N, the compound of formula (IIa) is prepared by a methodconsisting in reacting the aldehyde (III) and the lithium salt of theheterocycle (IVa):

More particularly, in the case where n=0, the compound of formula (II)is prepared by a method consisting in reacting the aldehyde (IIIa) andthe lithium salt of the 5-methylisoxazole derivative (IVa):

In the case where (X, Y) represents (S, N) or (NR₄, N), R₄ having thesame definition as above, it is possible to have the target molecules(IIa) by reacting the phenyloxirane derivatives (V) with the lithiumsalt of the 5-isothiazole derivative (compound (IV) with X=S and Y=N)and with the lithium salt of the 5-pyrazole derivative (compound (IV)with (X, Y)=(NR₄, N)), according to the scheme below. Such syntheses aredescribed in particular in: Ramacciotti, Alessio; Fiaschi, Rita;Napolitano, Elio; Tetrahedron asymmetry; 1996; 1101-1104:

In the case where the compound of formula (II) corresponds to formula(IIb) below in which R₁, R₂, R₃, X, Y and Z have the same definition asin formula (I):

the product (IIb) is advantageously prepared by a method characterizedin that:

in the case where X=O and Y=N, the aldehyde (VI) is reacted with alithium salt of the heterocycle (VII):

In the case where (X, Y) represents the pair of atoms (NR₄, N), R₄ beingas defined above, the procedure is essentially carried out according tothe scheme above using the method of protection described by Katritzkyet al.: Alan R. Katritzky, Ping Lue and Kunihiko Akutagawa, Tetrahedron45, 13 (1989), 4253-4262. The NH functional group of the pyrazole ringis protected with formaldehyde in order to avoid an N-alkylation. Theresulting N-protected pyrazole is treated with n-butyllithium to givethe lithium salt which, in the presence of aldehyde (VI), makes itpossible to obtain the products of formula (IIb).

When X=S and Y=N, the product (IIb) is obtained according to the methodsdescribed in the following articles: A. J. Layton and E. Lunt J. Chem.Soc. C 1968, 611-614 and Ashton, Michael J and al. J. Med. Chem., 27,10, 1984, 1245-1253. The isothiazole (VIII) is treated withn-butyllithium to give the lithium salt which in the presence ofaldehyde (VI) makes it possible to obtain a 5-alkylation so as tocorrespond to the products of formula (IIb₂).

Advantageously, according to the invention, the methods above apply tothe case where n=0.

Advantageously, according to the invention, the treatment of the product(II) in a basic alcoholic medium is characterized in that the alcohol inwhich the dehydration and the crystallization occur is ethanol, methanolor isopropyl alcohol. Advantageously still, the base which is added tothe alcohol is sodium hydroxide in the form of an aqueous solution.Preferably, the aqueous sodium hydroxide solution is a solution having aconcentration of between 0.1M and 5M, advantageously between 0.5M and4M, still more advantageously between 1M and 3M.

Preferably, the method comprises the following steps: dissolution of theproduct (II) in alcohol under reflux; addition of the base until thecompound (I) precipitates; addition of alcohol, still under reflux,until the precipitate is solubilized; cooling of the solution whichcauses crystallization of (I); filtration and washing of the crystals.

EXAMPLES I Synthesis of(E)-5-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)vinyl]-3-methylisoxazole

1.2 Reagents

The quantities of reagent are presented in table 1 below

TABLE 1 Reagents MW g/mol Eq. mmol Quantity 3,5-dimethylisoxazole 7.122.1 257.13     25 g (d = 0.99) n-butyllithium in  2.5 M 2.1 257.413  100 ml hexane 3,5-di-tert-butyl-4- 234.34  122.577 28.724 ghydroxybenzaldehyde THF 450 ml

1.3 Procedure:

n-Butyllithium (100 ml) is added (over 45 minutes) dropwise to asolution of 3,5-dimethyl-isoxazole (25 g) in THF (200 ml) cooled to −78°C. After stirring for 1 hour at −78° C.,3,5-di-tert-butyl-4-hydroxybenzaldehyde (27.724 g) in solution in THF(250 ml) is added dropwise over 3 hours. At the end of the addition, thereaction mixture is left for 2 h 30 min with stirring at −78° C.

The progress of the reaction is monitored by thin-layer chromatography:

Hexane/AcOEt Rf aldehyde Rf product (I) Rf product (II) 90/10 0.53 0.40.06 80/20 0.6 0.21

When the aldehyde has been consumed, the following treatment is carriedout:

-   concentration of the solvents (THF/hexane) by evaporation under    vacuum,-   taking up of the medium in 200 ml of ethyl acetate,-   washing with twice 100 ml H₂O (pH aqueous phase 7),-   concentration under vacuum.

The second part of the method in accordance with the invention comprisesthe following steps:

-   a) Recrystallization/dehydration EtOH/NaOH 2M    -   addition of 100 ml of ethanol, the mixture is heated under        reflux    -   addition of 2M NaOH until the product (I) precipitates (about        100 ml)    -   addition of ethanol until solubilization of (I) is obtained    -   filtration and washing of the crystals with 100 ml of H₂O and        100 ml of hexane.        (E)-5-[2-(3,5-Di-tert-butyl-4-hydroxyphenyl)vinyl]-3        -methylisoxazole is obtained with an overall yield relative to        the starting material which varies between 50% and 86%.-   b) Optionally, a recrystallization with EtOH (8 ml/g) is then    carried out    Mass obtained: 23.2 g/overall yield: 58%

II-Analysis of(E)-5-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)vinyl]-3-methylisoxazole

2.1 Structural Study

Structural formula of(E)-5-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)vinyl]-3-methylisoxazole:

2.1.1 Infrared Spectrum

The infrared spectrum is performed between 4000 and 400 cm⁻¹ on a KBrpellet containing about 1% of(E)-5-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)vinyl]-3-methylisoxazole

The principal peaks observed are:

-   3500 cm⁻¹: ν_(O-H)-   2850-2950 cm⁻¹: ν_(C-H) (tBu, CH₃, CH)-   1640, 1570 and 1440 cm⁻¹: ν_(C=C) and ν_(C=N)-   1230 and 1100 cm⁻¹: ν_(=C-O)-   960 cm⁻¹: ν_(N-O)-   The IR spectrum is in conformity with the expected structure.

2.1.2 NMR Spectrum

The ¹H NMR spectrum is performed on a solution in deuterated chloroformwith a 200 MHz spectrometer.

Solvent peaks: TMS: 0 ppm; H₂O: 1.55 ppm; CHCl₃: 7.24 ppm.

The peaks for the compound are analyzed in table 2 below:

TABLE 2 Chemical shift Multiplicity Integration Attribution 1.45 ppmsinglet 18 H 2 tBu  2.3 ppm singlet  3 H CH₃ at the 6-position  5.4 ppmsinglet  1 H OH  6.0 ppm singlet  1 H H₅ 6.75 ppm doublet  1 H H₄ with JH₃—H₄ = 16 Hz  7.2 ppm doublet  1 H H₃  7.3 ppm singlet  2 H H₁ and H₂

The NMR spectrum is in conformity with the expected structure.

2.1.3 Mass Spectrum

The mass spectrum is performed in “FAB positive” ionization with NBA(3-nitrobenzyl alcohol) for matrix.

The following ions are observed (table 3):

TABLE 3 m/z Attribution 313 M⁺ 314 (M + H)⁺ 627 (2 M + H)⁺

The mass spectrum is in conformity with the expected structure.

2.1 Identification

2.2.1 Melting Point

The melting point was measured on various batches, the results aresummarized in table 4 below:

TABLE 4 Batch No. Appearance Melting point Purity MC00III17 White grains189° C.  99.5% DG00IV53 White crystals 191° C. 100.7% DG00IV42 Whitecrystals 189° C. 100.7% DG00IV52 Yellow-white flakes 190° C.  99.8%MC00III11 Yellow-white grains 186° C.  97.6% MC99II159 Yellow-whitegrains 189° C. 100.3% DG01V21 Beige-yellow grains 188° C.  97.4%DG01V20.3 Beige-yellow 191° C.  96.7% crystals DG01V20.2 Pink grains187° C.  91.2%

It is observed that the melting point of(E)-5-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)vinyl]-3-methylisoxazole isin the range of 185-193° C.

Apart from batch DG01V20.2, all the batches have a purity greater than95% regardless of the appearance of the powder.

2.2.2 TLC

The TLC analysis is carried out under the following conditions:

-   -   F₂₅₄ silica plate    -   sample: 100 μl of solution at 0.4 mg/ml in MeOH    -   control at 1%: 20 μl of solution at 0.02 mg/ml    -   control at 5%: 100 μl of solution at 0.02 mg/ml    -   focusing: MeOH    -   elution: hexane 90/10 ethyl acetate    -   migration: about 5 cm    -   development: UV 254 nm and solution at 5% FeCl₃ in 0.5M HCl        (EtOH at 95%)    -   results:

X 254 nm:(E)-5-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)vinyl]-3-methylisoxazole hasa spot of high intensity at Rf: 0.30. The product of degradation alsohas a spot at Rf: 0.34.

X Developing agent FeCl₃: An orange-brown spot is obtained for(E)-5-[2-(3,5-di-tert-butyl-4-hydroxy-phenyl)vinyl]-3-methylisoxazole atthe same Rf on an orange-colored background for the plate.

2.2 Assay

2.3.1 Loss on Drying

The loss on drying makes it possible to determine the content of waterand of organic solvent. It is determined on 1 g if possible in an ovenat 100-105° C. for 3 h or until constant weight is obtained.

A weighed sample of the order of 1 g is introduced into a previouslydried crystallizing dish, and then the latter is placed in an oventhermostated at 100-105° C. for 3 h. The crystallizing dish is allowedto cool in a desiccator to room temperature. The crystallizing dish isweighed and the loss is calculated as % by the following formula:

${{Loss}\mspace{14mu}(\%)} = \frac{\left( {W - m} \right) \times 100}{W}$

with W: weighed amount introduced

m: mass after heating in an oven

2.3.2 HPLC Assay

Principle:

The isocratic HPLC technique allows the assay of(E)-5-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)vinyl]-3-methylisoxazoleunder conditions of specificity in relation to the two synthesisprecursors, to an unknown synthesis impurity and to the product ofdegradation by UV radiation.

Method:

The purity of(E)-5-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)vinyl]-3-methylisoxazole isdetermined by isocratic HPLC by external calibration and expressedrelative to the dry substance.

Procedure:

Materials:

Column: Lichrosphere C18, 5 μm, 100 A°, 125×4 mm+precolumn (4×4 mm)

Mobile phase: 250H20+750 MeOH(HPLC solvents)

Flow rate: 1 ml/min

Room temperature

Detector: 240 nm

Volume for injection: 25 μl

Integrator: ST=25 min, CS=2.5, SP=400, Noise=2, Sens=40, Att=4

Merck chain: L-6200A type pump

Injector AS-2000A type

Detector L-4250 type

Integrator D-2500 type

The(E)-5-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)-vinyl]-3-methylisoxazolecontrol was synthesized, purified and dried in the laboratory.

Results:

The HPLC analysis makes it possible to verify that the purity of theproduct obtained by the method according to the invention is greaterthan 98%.

1. A method for synthesizing derivatives corresponding to formula (I):

in which: R₁, R₂, R₃, at the 2, 3, 4, 5 or 6 position of the phenyl ring, which are identical or different, are chosen from: a hydrogen atom; C₁-C₆ alkyls; C₂-C₆ alkenyls; C₂-C₆ alkynyls; halogens, C₁-C₆ haloalkyls; —OH; the groups —OR′, —SH, —SR′, —SeH, —SeR′, —C(O)R′, —NHC(O)R′, —C(S)R′, —NHC(S)R′, —CN in which R′ represents a group chosen from C₁-C₆ alkyls, C₂-C₆ alkenyls, C₂-C₆ alkynyls; the groups —C(O)OR″, —OC(O)R″, —NR″R′″ in which R″ and R′″, which are identical or different, represent a group chosen from a hydrogen atom, C₁-C₆ alkyls, C₂-C₆ alkenyls, C₂-C₆ alkynyls; X and Y represent a pair of atoms chosen from: (NR₄, N) (pyrazole ring), (O, N) (isoxazole ring), (S, N) (isothiazole ring), R₄ being chosen from: a hydrogen atom; C₁-C₆ alkyls; the groups CH₂—OR₅, the groups C(O)OR₅ in which R₅ is chosen from a hydrogen atom, a C₁-C₆ alkyl group, a benzyl group; the heterocycle is linked to the phenyl ring via its 3- or 5- position in the case of the pyrazole ring, via its 5-position in the case of the isoxazole and isothiazole rings; n represents an integer chosen from 0, 1, 2, 3, 4, 5 and 6; Z, at the 3- or 4-position of the isoxazole, pyrazole or thioxazole ring, represents a group chosen from: a hydrogen atom; C₁-C₆ alkyls; C₂-C₆ alkenyls; C₂-C₆ alkynyls; halogens, C₁-C₆ haloalkyls; —OH; the groups —OR′, —SH, —SR′, —SeH, —SeR′, —C(O)R′, —NHC(O)R′, —C(S)R′, —NHC(S)R′, —CN in which R′ represents a group chosen from C₁-C₆ alkyls, C₂-C₆ alkenyls, C₂-C₆ alkynyls; the groups —C(O)OR″, —OC(O)R″, —NR″R′″ in which R″ and R′″, which are identical or different, represent a group chosen from a hydrogen atom, C₁-C₆ alkyls, C₂-C₆ alkenyls, C₂-C₆ alkynyls, this method being characterized in that it comprises at least one step consisting in treating the product corresponding to formula (II) below in which R_(1,) R_(2,) R_(3,) X, Y, Z and n have the same definition as in formula (I) above, in alcohol in the presence of a base to give the product of formula (I):

A and B being chosen such that one of A and B is H, the other being —OH.
 2. The method as claimed in claim 1, characterized in that at least one of the conditions below is met: R₁, R₂, R₃ are at the 3-, 4- or 5-position of the phenyl ring; R₁, R₂, R₃ are chosen from: a hydrogen atom; C₁-C₆ alkyls; halogens; C₁-C₆ haloalkyls; —OH; the groups —OR′, in which R′ represents a group chosen from C₁-C₆ alkyls; the groups —OC(O)R″, in which R″ represents a group chosen from a hydrogen atom, C₁-C₆ alkyls; X =O; Y =N; n=0; Z is at the 3-position of the heterocycle, Z represents a group chosen from: C₁-C₆ alkyls; halogens; C₁-C₆ haloalkyls.
 3. The method as claimed in claim 1, characterized in that the conditions below are met: A=OH, B =H.
 4. The method as claimed in claim 2, characterized in that at least one of the conditions below is met: the heterocycle represented by formula:

is a Z-substituted derivative of 5-isoxazole; R₁ at the 3-position is a tert-butyl group; R₂ at the 4-position is a hydroxyl group; R₃ at the 5-position is a tert-butyl group; Z at the 3-position is a methyl group.
 5. The method as claimed in claim 4, characterized in that the product (I) is (E)-5-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)vinyl]-3-methylisoxazole.
 6. The method as claimed in claim 1, characterized in that the alcohol in which the dehydration and the crystallization are performed is ethanol, methanol or isopropyl alcohol.
 7. The method as claimed in claim 1, characterized in that the base which is added to the alcohol is sodium hydroxide in the form of an aqueous solution.
 8. The method as claimed in claim 7, characterized in that the aqueous sodium hydroxide solution is a solution having a concentration of between 0.1 M and 5 M.
 9. The method as claimed in claim 1, characterized in that it comprises the following steps: dissolution of the product (II) in alcohol under reflux; addition of the base until the compound (I) precipitates; addition of alcohol, still under reflux until the precipitate is solubilized; cooling of the solution which causes crystallization of(I); filtration and washing of the crystals.
 10. The method as claimed in claim 1, comprising a step for preparing a compound of formula (II) in which A =OH and B =H, and in which X =O and Y =N, characterized in that the aldehyde (III) and the lithium salt of the heterocycle (IVa) are reacted in order to obtain the derivative (IIa₁):

R₁, R₂, R₃ and Z having the same definition as in formula (II).
 11. The method as claimed in claim 1, comprising a step for preparing a compound of formula (II) in which A =OH and B =H, and in which (X, Y) represents (S, N) or (NR₄, N), R₄ having the same definition as in formula (II), characterized in that a phenyloxirane (V) derivative is reacted with the lithium salt of the 5-isothiazole derivative (compound (TV) with X=S and Y=N) or with the lithium salt of the 5-pyrazole derivative (compound (IV) with (X, Y)=(NR₄, N)), according to the scheme below:


12. The method as claimed in claim 8, wherein the aqueous sodium hydroxide solution has a concentration of between 0.5M and 4M.
 13. The method as claimed in claim 8, wherein the aqueous sodium hydroxide solution has a concentration of between 1M and 3M. 